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Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma.
Thyroid 2014; 24(8):1256-66T

Abstract

BACKGROUND

RET/PTC rearrangement, RAS, and BRAF mutations are considered to be mutually exclusive in papillary thyroid carcinoma (PTC). However, although concomitant mutations of RET/PTC, RAS, or BRAF have been reported recently, their significance for tumor progression and survival remains unclear. We sought to examine the prognostic value of concomitant mutations in PTC.

METHODS

We investigated 88 PTC for concomitant mutations. Mutation in BRAF exon 15, KRAS, NRAS, and HRAS were studied by polymerase chain reaction (PCR)-sequencing of tumor DNA; RET/PTC rearrangement was determined by reverse transcription (RT)-PCR-sequencing of tumor cDNA.

RESULTS

BRAF(V600E) was detected in 39 of 82 classic PTC (CPTC) and in all three tall-cell variants (49%, 42/85). KRAS mutation (p.Q61R and p.S65N) was detected in two CPTC (2%, 2/88) and NRAS(Q61R) in one CPTC and two follicular variant PTC (FVPTC; 3%, 3/88). KRAS(S65N) was identified for the first time in thyroid cancer and could activate mitogen-associated protein kinase (MAPK). RET/PTC-1 was detected in nine CPTC, one tall-cell variant, and two FVPTC. Concomitant BRAF(V600E) and KRAS, or BRAF(V600E) and RET/PTC-1 mutations were found in two CPTC, and six CPTC and one tall-cell variant, respectively. In total, 11 concomitant mutations were found in 88 PTC samples (13%), and most of them were in the advanced stage of disease (8/11, 73%; p<0.01).

CONCLUSIONS

Our data show that concomitant mutations are a frequent event in advanced PTC and are associated with poor prognosis. The concomitant mutations may represent intratumor heterogeneity and could exert a gene dosage effect to promote disease progression. KRAS(S65N) can constitutively activate the MAPK pathway.

Authors+Show Affiliations

1 Department of Genetics, King Faisal Specialist Hospital and Research Centre , Riyadh, Saudi Arabia .No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24798740

Citation

Zou, Minjing, et al. "Concomitant RAS, RET/PTC, or BRAF Mutations in Advanced Stage of Papillary Thyroid Carcinoma." Thyroid : Official Journal of the American Thyroid Association, vol. 24, no. 8, 2014, pp. 1256-66.
Zou M, Baitei EY, Alzahrani AS, et al. Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma. Thyroid. 2014;24(8):1256-66.
Zou, M., Baitei, E. Y., Alzahrani, A. S., BinHumaid, F. S., Alkhafaji, D., Al-Rijjal, R. A., ... Shi, Y. (2014). Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma. Thyroid : Official Journal of the American Thyroid Association, 24(8), pp. 1256-66. doi:10.1089/thy.2013.0610.
Zou M, et al. Concomitant RAS, RET/PTC, or BRAF Mutations in Advanced Stage of Papillary Thyroid Carcinoma. Thyroid. 2014;24(8):1256-66. PubMed PMID: 24798740.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma. AU - Zou,Minjing, AU - Baitei,Essa Y, AU - Alzahrani,Ali S, AU - BinHumaid,Faisal S, AU - Alkhafaji,Dania, AU - Al-Rijjal,Roua A, AU - Meyer,Brian F, AU - Shi,Yufei, Y1 - 2014/06/10/ PY - 2014/5/7/entrez PY - 2014/5/7/pubmed PY - 2015/4/1/medline SP - 1256 EP - 66 JF - Thyroid : official journal of the American Thyroid Association JO - Thyroid VL - 24 IS - 8 N2 - BACKGROUND: RET/PTC rearrangement, RAS, and BRAF mutations are considered to be mutually exclusive in papillary thyroid carcinoma (PTC). However, although concomitant mutations of RET/PTC, RAS, or BRAF have been reported recently, their significance for tumor progression and survival remains unclear. We sought to examine the prognostic value of concomitant mutations in PTC. METHODS: We investigated 88 PTC for concomitant mutations. Mutation in BRAF exon 15, KRAS, NRAS, and HRAS were studied by polymerase chain reaction (PCR)-sequencing of tumor DNA; RET/PTC rearrangement was determined by reverse transcription (RT)-PCR-sequencing of tumor cDNA. RESULTS: BRAF(V600E) was detected in 39 of 82 classic PTC (CPTC) and in all three tall-cell variants (49%, 42/85). KRAS mutation (p.Q61R and p.S65N) was detected in two CPTC (2%, 2/88) and NRAS(Q61R) in one CPTC and two follicular variant PTC (FVPTC; 3%, 3/88). KRAS(S65N) was identified for the first time in thyroid cancer and could activate mitogen-associated protein kinase (MAPK). RET/PTC-1 was detected in nine CPTC, one tall-cell variant, and two FVPTC. Concomitant BRAF(V600E) and KRAS, or BRAF(V600E) and RET/PTC-1 mutations were found in two CPTC, and six CPTC and one tall-cell variant, respectively. In total, 11 concomitant mutations were found in 88 PTC samples (13%), and most of them were in the advanced stage of disease (8/11, 73%; p<0.01). CONCLUSIONS: Our data show that concomitant mutations are a frequent event in advanced PTC and are associated with poor prognosis. The concomitant mutations may represent intratumor heterogeneity and could exert a gene dosage effect to promote disease progression. KRAS(S65N) can constitutively activate the MAPK pathway. SN - 1557-9077 UR - https://www.unboundmedicine.com/medline/citation/24798740/Concomitant_RAS_RET/PTC_or_BRAF_mutations_in_advanced_stage_of_papillary_thyroid_carcinoma_ L2 - https://www.liebertpub.com/doi/full/10.1089/thy.2013.0610?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -